Sensory information reaching the brain is processed by region-restricted neural networks leading to learning and adaptation to a constantly changing environment. Recent studies have elucidated some of the general molecular mechanisms underlying learning and memory;however, it becomes increasingly clear that there are gene networks that uniquely position key neural circuits to control specialized behaviors. The long-term goal of this work is to systematically characterize how gene regulatory networks control neural circuits dedicated to learned fear. More specifically, this proposal is focused on a gene, gastrin-releasing peptide (GRP), that this laboratory has previously identified as expressed in the neural circuits specifically involved in processing fear- related conditioned stimulus (CS) information. Recently published work from this laboratory suggests that GRP and neuronal circuits that express GRP have an important role in fear memory. The hypothesis will be tested that GRPergic neural circuitry is involved in unimodal and multimodal types of fear memory. A multidisciplinary approach that combines mammalian genetics, behavior and electrophysiology will be used to address the following Specific Aims. Aim 1 will ask whether GRP in the amygdala regulates fear memory. GRP knockout mice will be analyzed in amygdala synaptic plasticity and memory in fear conditioning. The anatomic site of GRP function will be examined by GRP administration in the amygdala of the GRP knockout mice. Aim 2 will ask whether selective elimination of the GRPergic neurons in two different areas of the amygdala differentially affects unimodal and multimodal memories of fear. Aim 3 will ask whether there are two GRP expressing neural microcircuits in the amygdala processing differentially unimodal and multimodal fear memories. GRP and GRPR can be used to develop drugs, targeting neural circuits dedicated to fear and anxiety, and thus more effective interventions can be envisioned that lack side effects. PUBLIC HEALTH RELEVANCE Gastrin-releasing peptide (GRP) may be used to design drugs for the selective regulation of learned fear- related behaviors. Moreover, GRP knockout mice can be used to study how memory of fear is involved in borderline personality disorder, PTSD and generalized anxiety disorder.